Otger Campàs, PhD
Mechanical determinants of tooth formation

Link to Otger's Website

Co-mentors:

Donald Ingber, MD, PhD
Judah Folkman Professor, Dept. of Pathology
Interim Co-Director, Vascular Biology Program
Children's Hospital Boston
Harvard Medical School

Lakshminarayanan Mahadevan, PhD
Lola England Professor of Applied Mathematics
Harvard School of Engineering and Applied Sciences

PhD

Institut Curie (Paris) and University of Barcelona
(Biophysics), 2006
Advisors: Jacques Prost, PhD; Jean-François Joanny, PhD; Jaume Casademunt, PhD

BS

University of Barcelona
(Physics), 2002

The ultimate functional morphology of a tissue is governed by both signaling molecules and physical forces. Understanding how mechanics and gene expression act together to shape tissues would be of capital importance to design ways in which developmental processes could be guided to engineer organ morphology. In order to address these questions we will focus on tooth formation because the signaling molecules that orchestrate the different stages of development are relatively well known and also because it is simple enough for theoretical treatment. As a SysCODE fellow I will approach tooth development from two different, but complementary, perspectives:
1) Describe mathematically the initial stages of tooth formation (bud stage) and identify the physical parameters that are relevant for tooth morphogenesis;
2) Develop an experimental set-up to measure the mechanical properties of growing tissues in 3 dimensions. We will use force transducers that provide a direct readout of the forces in different locations of the growing tissue.

Behzad Gerami-Naini, PhD
Tooth formation from human embryonic stem cells in a three-dimensional (3D) in vitro model

Co-mentors:

Richard Maas, MD, PhD
Professor of Medicine, Division of Genetics,
Brigham and Women's Hospital, Harvard Medical School;
SysCODE Consortium Director

David Mooney, PhD
Professor of Bioengineering
Harvard School of Engineering and Applied Sciences

PhD

University of Wisconsin at Madison
(Endocrinology-Reproductive Physiology), 2006

BS

University of Texas at Arlington
(Biological Sciences), 1994

The mammalian dentition, like many organs, develops through a series of sequential and reciprocal interactions between epithelial and mesenchymal tissues. The ability of human embryonic stem cells (hESCs), mouse embryonic stem cells (mESCs) and induced pluripotent stem cells (iPS cells) to differentiate into various cell types in vitro, such as neural progenitors, pancreatic progenitors, and trophoblast cells provides a powerful platform to study mechanisms of organogenesis such as those mediating odontogenesis, in vitro. In my project, I will test the hypothesis that under correct spatial and temporal programming of the cellular microenvironment, hESCs can be directed along the odontogenic pathway to form tooth germs in vitro. This hypothesis will be tested using the following two specific aims. Specific Aims: a) To investigate whether three-dimensional (3D) epithelial-mesenchymal interactions can augment the odontogenic differentiation of hESCs, mESCs and iPS cells. b) To evaluate the role of specific signaling molecules on the directed differentiation of stem cells within these 3D extracellular matrix (ECM) arrays.

Yinghua Guan, PhD
Applied single molecular imaging techniques in vitro and in vivo

Co-mentors:

Jagesh Shah, PhD
Asst. Professor, Dept. of Systems Biology
and Dept. of Medicine, Harvard-MIT Div. of HST
Renal Division, Dept. of Medicine,
Brigham and Women's Hospital
Director, Laboratory for Cellular Systems Biology
and Molecular Imaging, Harvard Medical School

Sangeeta Bhatia, MD, PhD
Professor, Dept. of Electrical Engineering
and Computer Science
Director, Laboratory for Multiscale
Regenerative Technologies, Harvard-MIT Div. of HST

PhD

Peking University, China
(Physical Chemistry), 2006

BS

Beijing Normal University, China
(Chemistry), 2000

It has been a significant challenge to quantitatively study the dynamic intracellular processes in live cells. These studies are essential for a thorough understanding of the underlying mechanisms regulating the signaling pathways and the transitions during cell proliferation and differentiation. As a SysCODE fellow I will apply my knowledge in single molecule detection instruments - confocal, wide-field and total internal reflection fluorescence microscopy - to study cell transformation, proliferation and differentiation during early odontogenesis by using single molecule and cell imaging technique in vitro and in vivo. The key element of this study will be to provide a comprehensive dynamic description of the live cell transformation under mechanical or chemical stress monitored with a number of known genetic markers. Specific aims: 1) Use quantitative models for cell behavior developed in Dr. Shah and Dr. Bhatia laboratories to measure degree of morphological changes in cell during early odontogenesis; 2) Study temporal kinetics for alleles known to be involved in odontogenesis (Pax9, Wnt, Msx, etc.) to validate and/or complement the construction of gene regulatory network (GRN) with live cell information; 3) Provide Proof of Principle results for reporter cell imaging protocol that can be adopted by other SysCODE teams.

Joshua Ho, PhD
Integrative ChIP-seq analysis for developmental biology

Co-mentors:

Peter Park, PhD
Assistant Professor, Dept. of Pediatrics
Associate Director of Bioinformatics
Harvard-Partners Center for Genetics and Genomics
Brigham and Women's Hospital
Children's Hospital Boston
Harvard Medical School

Richard Maas, MD, PhD
Professor of Medicine, Division of Genetics,
Brigham and Women's Hospital, Harvard Medical School;
SysCODE Consortium Director

PhD

University of Sydney, Australia
(Bioinformatics), 2010

BS

University of Sydney, Australia
(Biochemistry and Computer Science), 2006

Stem cell differentiation is regulated by a set of highly coordinated regulatory pathways mediated by various protein-DNA events at the genomic and epigenomic levels. Recently, large-scale genome-wide mapping of various in vivo protein-DNA interactions has been made possible by advances in chromatin immunoprecipitation (ChIP) followed by massively parallel sequencing (ChIP-seq). However, we currently do not have a systematic analysis framework for comparing and integrating multiple ChIP-seq profiles in the context of two-group, multi-group, factorial, and time-series experimental designs that are pertinent to many developmental biology studies. In this project, I aim to develop practical bioinformatics methods for analysis of ChIP-seq profiles, and systematically apply them to understand the gene regulatory dynamics underlying organ development. In particular, I will leverage the data being generated from various participating and collaborating laboratories of SysCODE to build an integrative view of the molecular mechanisms leading to the development of heart valve, tooth germs, and pancreatic islets.

Chong Wee Liew, PhD
Analyses of the islet proteome

Co-mentors:

Rohit Kulkarni, MD, PhD
Assistant Professor of Medicine, Joslin Diabetes Center

Steven Gygi, PhD
Assistant Professor of Cell Biology, Harvard Medical School
Director, Taplin Biological Mass Spectrometry Facility

PhD

University of Hamburg, Germany
(Cell Biology), 2005
Advisor: Hans-Juergen Kreienkamp

BS

National University of Singapore, Singapore
(Microbiology), 1996

The pancreatic islets of Langerhans, and especially the insulin-producing beta cells, play a central role in the maintenance of glucose homeostasis. The proposed experiments will allow the generation of a novel data base of proteins and gene expression in the endocrine pancreas (islets and beta cells) of a mammalian model (the mouse) -from adults and animal at different pancreatic islets maturation periods. These data will be useful for planning mammalian tissue engineering for pancreatic islets with specific reference to pancreatic beta cells. Specific Aims: a) A proteomic approach to identify the proteins in adult islets isolated from male mice on a pure C57Bl/6 genetic background. Due to the reason that islets constitute only ~2% of the pancreas we will use this initial set of experiments to generate data and in parallel standardize the methodology and fine-tune the technique to improve total protein yield. b) Subsequent studies will utilize islets pooled from appropriate numbers of male mice at distinct islets maturation stages as well as sorted beta cells from isolated adult islets. c) In subsequent periods of the Program we will focus on characterizing the proteome using islets from models that exhibit beta cell expansion.

David Nusinow, PhD
Computational Methods for Proteomic Data Analysis

Co-mentors:

Shamil Sunyaev, PhD
Assistant Professor, Dept. of Medicine
Harvard-MIT Division of HST
Division of Genetics, Dept. of Medicine
Brigham and Women's Hospital
Harvard Medical School

Richard Maas, MD, PhD
Professor, Dept. of Medicine
Division of Genetics, Dept. of Medicine
Brigham and Women's Hospital
Harvard Medical School

PhD

Sackler School of Graduate Biomedical Science at Tufts University
(Cell, Molecular, and Developmental Biology), 2008

BS

University of California
(Molecular, Cell, and Developmental Biology), 2002

Proteomic methods present the opportunity to sharpen our global view of biological processes. However, developmental biologists have yet to widely embrace proteomics due to various difficulties with the methods. Perhaps the most notable difficulties include analyzing and interpreting the data from such experiments. One goal of the SysCODE project is to use proteomic data to understand organ composition, but to do so we must overcome these hurdles and find ways to integrate findings from proteomic experiments with that of whole-genome gene expression studies and classical genetic models. The goal of my project is to develop methods to do this, and apply them to the analysis of the mammalian organs that are the focus of the SysCODE effort. These analyses will be applied to further experimental design, and provide a cohesive framework to utilize proteomics in the study of organ development.

Alex Rolfe, PhD
Computational Discovery of Regulatory Networks in Pancreatic Islets

Co-mentors:

David Gifford, PhD
Professor, Dept. of Electrical Engineering and Computer Science, Computer Science and Artificial Intelligence Laboratory, MIT

Doug Melton, PhD
Cabot Professor and Founding Chair, Dept. of Stem Cell and Regenerative Biology, Harvard University
Investigator, Howard Hughes Medical Institute
Co-Director, Harvard Stem Cell Institute

PhD

MIT
(Computer Science), 2009
Advisors: Profs. David Gifford, Gerry Fink, Tommi Jaakkola, and Ernest Fraenkel

BS

MIT
(Computer Science), 2001

Much of the work in regulatory network discovery has focused on integrating expression data, binding data, and motif presence to detect regulatory relationships, modules, and programs. Recent work in our lab and others has demonstrated the existence and importance of overlapping and interfering transcripts as regulatory mechanisms. I plan to use RNASeq experiments performed on pancreatic islets to identify examples of these mechanisms. By combining these newer mechanisms with our existing models, we should be able to more accurately explain the key features of gene regulation in the pancreas.

The second focus of my work will be smaller networks that incorporate disparate data sources, for example metabolic pathway and protein interaction databases. Since these databases are often incomplete, we must adapt our computational methods to work around missing information and produce more detailed results for smaller sets of genes.

Richard Sherwood, PhD
Building a Transcriptional and Signaling Network of Pancreatic Specification

Co-mentors:

Richard Maas, MD, PhD
Professor of Medicine, Division of Genetics,
Brigham and Women's Hospital, Harvard Medical School;
SysCODE Consortium Director

David Gifford, PhD
Professor, Dept. of Electrical Engineering and Computer
Science, Computer Science and Artificial Intelligence
Laboratory, MIT

PhD

Harvard University
(Molecular and Cellular Biology), 2009
Advisor: Dr. Douglas Melton

BS

Stanford University
(Biological Sciences), 2004

While embryonic stem (ES) cells have been touted as a promising therapeutic tool, their efficient differentiation into therapeutically relevant cell types has yet to be achieved. The root cause behind this failure is the lack of understanding of how cells are progressively specified during normal embryonic development. The goals of my project are twofold: to advance ES cell differentiation toward therapeutically relevant pancreatic cell types and to understand basic developmental processes such as cell fate specification and determination at a molecular level. In order to achieve these goals, I have broken down development along the pancreatic lineage into discrete steps based on a detailed understanding of embryonic pancreatic development, and I am focusing on obtaining a mechanistic understanding of how intercellular signaling pathways and transcription factors, the master regulator genes of development, coordinate each progressive step both in embryos and in ES cells. I use techniques such as chromatin immunoprecipitation followed by high- throughput sequencing (ChIPseq), co-immunoprecipitation followed by mass spectrometry (IP-MS), and genome-wide transcriptional profiling to understand where relevant developmental transcription factors bind in the genome, what their transcriptional partners are, and how they affect expression of all other genes. I am collaborating with computational biologists to build a predictive model of development that combines cell signaling inputs and transcriptional interactions discovered in our system.

Peggi Angel, PhD
Heart valve proteome during organ development in vitro

Co-mentors:

Scott Baldwin, MD
Katrina Overall McDonald Professor, Dept. of Medicine
Chief of Division of Pediatric Cardiology, Vanderbilt University Medical Center

Richard Caprioli, PhD
Stanley Cohen Professor, Dept. of Biochemistry
Director, Mass Spectrometry Research Center
Vanderbilt University School of Medicine
Professor, Dept. of Chemistry and Dept. of Pharmacology
Vanderbilt University

PhD

University of Georgia
(Analytical Chemistry), 2007
Advisor: Ronald Orlando, PhD

BS

Georgia Southern University
(Chemistry), 1999

Abnormal heart valve formation affects over 1% of the US population and is a primary cause of prenatal and postnatal death. Although morphological progression of heart valve development has been well studied, the molecular factors that guide this process are poorly defined. Our goal is to produce a comprehensive proteomic portrait of early mouse heart valve development. A key element of this goal is the identification of proteins important to endothelial-mesenchymal transformation, a process that is critical not only to early valve cushion formation but to other major developmental events such as tooth germ formation. The data will be made available for comparison to tooth germ formation and pancreatic islet formation to better understand the developmentally important endothelial-mesenchymal transformation. Information from this study will be directly applicable to tissue engineering approaches to heart valve formation.

Kaustabh Ghosh, PhD
Engineered microenvironments for in situ pancreatic islet generation

Co-mentors:

Donald Ingber, MD, PhD
Judah Folkman, Professor, Dept. of Pathology
Vascular Biology Program
Children's Hospital Boston, Harvard Medical School

Robert S. Langer, PhD
Institute Professor
Dept. of Chemical and Biomedical Engineering, MIT

PhD

State University of NY at Stony Brook
(Biomedical Engineering), 2006
Advisor: Richard A.F. Clark, MD

B.Tech

National Institute of Technology, India
(Technology), 2001

Diabetes, which poses major health and financial burden, arises from the loss of insulin production by ß cells of the islets of Langerhans. Islet transplantation, however, has had limited success in restoring normal islet function, largely due to post-transplantation challenges such as immune rejection, loss of islet cell viability and lack of optimal vascularization, thus suggesting the need to develop alternate therapies. For this proposal, I will seek to identify micro-environmental (chemical as well as physical) determinants that promote EPC adhesion, proliferation and differentiation into mature functional endothelium, and use these findings as design criteria to fabricate multi-functional biomaterials that will induce endothelium-mediated pancreatic islet normalization and/or survival of transplanted ß cells when targeted to diseased islets in the body.